There has been for many years an ongoing search for the discovery and development of more effective antiinflammatory and hypothermia inducing agents which can be administered to mammals in therapeutically effective dosages with minimal side effects. There is also an economic need for such agents which are relatively simple to produce from readily available non-costly reagents. A wide variety of compounds have demonstrated antiinflammatory properties, as for example pyrazolidinediones, arylalkanoic acids, carboxylic acid amides, and salicylates. Anthranilic acid and certain of its derivatives, such as mefenamic acid, flufenamic acid, and N-benzoyl-anthranilic acid, have also exhibited antiinflammatory activity as described, for example in the article by M. W. Whitehouse, "Biochemical Properties of Anti-Inflammatory Drugs," Biochem. Pharmacol., 16, pp. 753-760 (1967). Aspirin, of course, is probably the most commonly used antiinflammatory and antipyretic agent. Most of the known antipyretics have the disadvantage of often dangerous side effects such as causing circulatory collapse.
The compound 2-methyl-2(4-methyl-pent-3-enyl)-5-hydroxy-7-pentylchromene or cannabichromene (CBC) is well-known in the prior art, occurring naturally as a cannabinoid constituent of Cannabis sativa L. The reported usefulness of cannabichromene is primarily that of intermediate in the synthesis of related compounds, such as cannabicyclol.
The known synthesis of cannabichromene have not been entirely satisfactory, owing to historical poor yields and problems associated with purification of the product.
Exemplary of such prior art synthesis routes are the cyclodehydrogenation of cannabigerol with chloranil in benzene or with 2,3-dichloro-5,6-dicyanobenzene (DDQ). Perhaps a more important route for the synthesis of cannabichromene and related compounds has been the condensation of citral with a substituted resorcinol. By this method, cannabichromene is formed by heating olivetol and citral for several hours under reflux in the presence of pyridine, in molar proportions of 1:1:1 (olivetol:citrol:pyridine), with isolation of the product by direct chromatography on silica gel. The yields obtainable by this method, however, have only about 15 to 17% of theory. Methods have been proposed to increase the yield of varying the proportion of pyridine employed; however, molar proportions of 1:1:3 have only slightly increased cannabichromene yield to 20%, and molar proportions of 1:1:6 have significantly decreased the yield to about 5%. The acid-catalyzed condensation of olivetol and citral is also known, but the products of this reaction are not known to include cannabichromene.
The pyridine-catalyzed olivetol/citral condensation reaction also provides significant amounts of at least five by-products, in addition to unreacted material from which the cannabichromene must be separated. Both unreacted citral and the by-product isobichromene present difficulties during cannabichromene recovery, owing to the nearly identical R.sub.f values of cannabichromene and citral in different solvent systems and the very close R.sub.f values on silica gel of cannabichromene and isocannabichromene.
Accordingly, it is an object of this invention to provide a new method of synthesizing cannabichromene.
It is another object of this invention to provide an improved method for the recovery of cannabichromene.
It is an additional object of this invention to provide a composition useful for inducing hypothermia and useful as an antiinflammatory agent.
It is a further object of this invention to provide a new compound, 2-methyl-2(4-methyl-pent-3-enyl)-5-hydroxy-7-methylchromene, or CBC-C.sub.1 as the compound will hereinafter be referred to.
It is an additional object of this invention to provide a method for reducing inflammation in mammals.
It is yet another object of this invention to provide a method for inducing hypothermia in mammals.